Sustained release dosage forms for oral administration, designed to deliver a pharmacologically active agent over an extended time period, are well known. In particular, dosage forms that are capable of delivering drug to the stomach and gastrointestinal tract in a controlled, “sustained release” manner are described in U.S. Pat. Nos. 5,007,790 to Shell, 5,582,837 to Shell and 5,972,389 to Shell et al., all of common assignment herewith. The dosage forms described in the aforementioned patents are comprised of particles of a hydrophilic, water-swellable polymer with the drug dispersed therein. The polymeric particles in which the drug is dispersed absorb water, causing the particles to swell, which in turn promotes their retention in the stomach and also allows the drug contained in the particles to dissolve and then diffuse out of the particles. The polymeric particles also release drug as a result of physical erosion, i.e., degradation.
Release of certain types of pharmacologically active agents or fragments thereof into the lower gastrointestinal tract is not desirable and may be detrimental to a number of patients. Release of antibiotics into the colon, for example, may disrupt the delicate balance of the natural flora and result in conditions such as pseudomembranous colitis. Most oral dosage forms, especially controlled release dosage forms, have the potential to deliver a significant amount of drug to the lower gastrointestinal tract and colon.
It has now been discovered that erodible, swellable dosage forms akin to those described in the '790, '837 and '389 patents may be modified so that drug delivery is targeted, i.e., the active agent is primarily released in the stomach and upper gastrointestinal tract, while release in the lower gastrointestinal tract and colon is minimal.
Representative active agents with which the present invention may be used are fluoroquinolone antibiotics, i.e., fluorinated analogs of nalidixic acid. These antibiotics are active against both gram-positive and gram-negative bacteria, and are believed to exert their therapeutic effect by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, thus blocking bacterial DNA synthesis. Fluoroquinolone antibiotics include ciprofloxacin, clinafloxacin, enoxacin, gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, sparfloxacin, trovafloxacin, and acid addition salts thereof.
Ciprofloxacin, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, is available commercially from the Bayer Corporation under the trade name Cipro®. Ciprofloxacin is of particular current interest, not only for its utility in treating opportunistic bacterial infections associated with HIV (e.g., infection with mycobacterium avium complex, or “MAC”), urinary tract infections (including those caused by multi-drug resistant bacteria such as Pseudomonas), bacterial diarrhea (caused, for example, by Shigella, Salmonella, toxigenic E. coli, or Campylobacter), tissue, bone and joint infections (e.g., caused by organisms such as Enterobacter), but also for its utility in inhibiting Bacillus anthracis, commonly known as “anthrax.” See, for example, D'iakov et al. (1994), “Comparative Evaluation of the Effectiveness of Fluoroquinolones in Experimental Anthrax Infection,” Antibiot. Khimioter. 39(6):15-19; Friedlander et al. (1993), “Postexposure Prophylaxis Against Experimental Inhalation Anthrax,” J. Infect. Dis. 167(5):1239-1243; Kelly et al. (1992) J. Infect. Dis. 166(5): 1184-1187. Ciprofloxacin is rapidly and well absorbed from the gastrointestinal (G.I.) tract, with an absolute bioavailability in the range of approximately 55% to 85%, typically around 70%. With the presently available immediate release dosage form, the maximum serum concentration is attained 1-2 hours after dosing and the serum half-life is approximately 4 hours. Ciprofloxacin and associated uses, synthetic methods, and formulations are described in U.S. Pat. Nos. 4,670,444, 4,705,789, 4,808,583, 4,844,902, 4,957,922, 5,286,754, 5,695,784, and 6,136,347.
The current ciprofloxacin dosage forms are administered once every twelve hours. Since the effect of ciprofloxacin persists longer than the 4-hour half-life of the drug (Davis et al. (1996) Drugs 51:1019-1074), extension of the duration of the plasma profile should, in theory, enable once daily delivery. However, design of a once daily dosage form with conventional sustained release dosage forms is problematic, because ciprofloxacin is poorly absorbed in the colon (Arder et al. (1990) Br. J. Clin. Pharmacol. 30:35-39) and delivery of any antibiotic to a healthy colon may lead to enterocolitis (Schact et al. (1988) Infection 16:S29), as alluded to above.
There is accordingly a need in the art to provide gastric retentive dosage forms wherein drug release in the lower gastrointestinal tract and colon is restricted, and the majority of the drug dose is delivered to the stomach and upper gastrointestinal tract. The invention is useful not only in conjunction with the delivery of ciprofloxacin, fluoroquinolone antibacterial agents in general, and other antibiotics, but also with a host of active agents for which restricted delivery in the lower intestinal tract is desirable.